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Numerous changes are now occurring in the pharmaceutical industry, not just in the way that the industry is perceived, but also in the rapid expansion of biomedical and scientific knowledge, which affects the way science is practiced in the industry. The recent changes in the way that synthetic chemistry is prac- ticed in this environment center around new scientific advances in synthetic techniques and new technologies for rational drug de- sign, combinatorial chemistry, automated synthesis, and compound purification and identification. In addition, with the advent of high-throughput screening (HTS), we are now faced with many targets being screened and many hits being evaluated. However, success in this arena still requires skilled medicinal chemists making the correct choic- es, often with insight gleaned from interac- tions with computational chemists and struc- tural biologists, about which “hits” (1) are likely to play out as true “lead” (1) structures that will meet the plethora of hurdles that any drug candidate must surmount. In the recent past, the usual flow of informa- tion that was generated regarding any new com- pound prepared in the laboratory of a drug dis- covery company followed a paradigm similar to that shown in Fig. 1. This scheme was driven by the need to get the initial information on a com- pound first, before deciding whether its proper- ties met appropriate criteria before moving onto the next evaluation step. Such a linear sequence of events, although sparing of the number of compounds taken down the pathway, often meant that a considerable amount of time passed (several weeks) before it was known whether a particular change in a molecule was in fact a use- ful transformation, or whether it was a potency- enhancing change in the primary in vitro assay but was perhaps a liability in a downstream evaluation. Thus, the delay in getting appropriate feedback to the synthetic chemist meant that decisions about which molecules to prepare in the next round of synthesis were not guided by input from downstream data. With the advent of faster synthetic technologies, including advances in nuclear magnetic resonance (NMR) methods, 1 Department of Basic Chemistry, Merck Research Lab- oratories, 126 East Lincoln Avenue, Rahway, NJ 07065, USA. 2 Department of Drug Metabolism, Merck Research Laboratories, Sumneytown Pike, West Point, PA 19486, USA. *To whom correspondence should be addressed. E- mail: malcolm_maccoss@merck.com D RUG D ISCOVERY 19 MARCH 2004 VOL 303 SCIENCE www.sciencemag.org 1810 S PECIAL S ECTION